Keratinocyte growth factor (KGF) is a member of the fibroblast growth factor (FGF) family, but acts only on cells of epithelial origin. We first characterized the KGF receptor (KGFR) on BALB/MK keratinocytes and in so doing, established the existence of at least two distinct receptors for acidic FGF (aFGF): that expressed by NIH/3T3 fibroblasts, which also binds basic FGF (bFGF), and that on BALB/MK, which also binds KGF. We later isolated the KGF receptor (KGFR) cDNA by an expression cloning strategy in which a BALB/MK cDNA library was used to transfect NIH/3T3 cells, which secrete KGF. KGFR cDNA transfectants were identified as transformed foci in which KGFR expression had created an autocrine growth loop. The human KGFR cDNA is identical to FGF receptor-2 (FGFR-2), except for 49 amino acids in the second half of the third Ig loop of the ligand-binding domain. Unlike the KGFR, which binds KGF and aFGF with high affinity, FGFR-2 bound aFGF and bFGF with high affinity, but not KGF. PCR analysis of genomic DNA demonstrated that the divergent region between the KGFR and FGFR-2 was determined by single alternative exons, which encoded the portion of the extracellular domains responsible for their different ligand binding properties. Hepatocyte growth factor (HGF) is a plasminogen-like protein that acts on endothelial cells, hepatocytes and a variety of epithelial cell types. We have previously identified the c-met proto-oncogene product as a cell- surface receptor for HGF. The interaction of HGF with the c-met receptor tyrosine kinase stimulates the phosphorylation of several yet unknown cellular proteins, which we are attempting to purify and characterize. We have also isolated and characterized a truncated form of HGF (NK2) which competes with full-length HGF for binding to c-met, and antagonizes its mitogenic action. The molecular basis for the opposing biological properties of HGF and NK2 is presently under investigation.